The present invention relates to novel compounds for the treatment of Parkinson disease and other conditions associated with impaired dopaminergic signaling in the brain, and, more particularly, to L-DOPA derivatives, which can serve as efficient L-DOPA prodrugs for treating such conditions.
Parkinson's disease (PD) is a common neurological syndrome characterized by the selective loss of dopaminergic neurons in the nigrostriatal tract, a selective site in the brain. Specifically, dopamine neurons in the substantia nigra degenerate, resulting in the loss of dopamine (3,4-dihydroxyphenethylamine) input to the striatum. In addition to the loss of dopaminergic neurons, other regions in the brain are affected, impairing vital activities. Altogether, the reduction of dopamine in the striatum and the impaired activity in other brain regions cause sever clinical symptoms such as increased muscle rigidity, resting tremor, bradykinesia, abnormalities of posture and gait, slowness of voluntary movement and slurred speech. The level of decrease in dopamine synthesis correlates with the severity of the symptoms. Without treatment, PD patients eventually progress to a tragically debilitating rigid state.
Current treatment regimes for PD consist primarily of pharmacological supplementation of the dopaminergic loss, preferably with dopamine agonists and levodopa (also known as 3-hydroxy-L-tyrosine, 3,4-dihydroxy-L-phenylalanine and L-DOPA). L-DOPA is the metabolic precursor of dopamine, which, unlike dopamine, can readily cross the blood-brain barrier. Administration of L-DOPA therefore results in increased levels thereof in the brain, where it is converted to dopamine by the enzyme Aromatic L-Amino Acid Decarboxylase (AADC). L-DOPA thus plays a major role in replenishing the loss of dopamine and is typically administered in combination with a DOPA decarboxylase inhibitor that inhibits decarboxylation of L-DOPA in the periphery (for a general review of PD treatments currently in use see Adams et al., Principles of Neurology 4th Ed. McGraw Hill, New York 1989).
However, conventional treatments for Parkinson's disease with L-DOPA have proven to be inadequate for many reasons of record in the medical literature. The systemic administration of levodopa, although producing clinically beneficial effects at first, is complicated by the need to reduce dosages that were well tolerated at the outset in order to avoid adverse side effects. Some patients also become less responsive to levodopa, so that previously effective doses eventually fail to produce any therapeutic benefit. For such reasons, the benefits of levodopa treatment often begin to diminish after about 3 or 4 years of therapy irrespective of the initial therapeutic response.
In addition, the augmentation of systemic levels of levodopa, necessary to establish therapeutically effective levels at the site of interest, i.e., the brain, have been reported to cause several gastrointestinal adverse effects (including anorexia, nausea and vomiting due to the stimulation of an emetic center located in the brain stem outside the blood-brain barrier), cardiovascular effects (mostly due to the increased catecholamine formation peripherally), dyskinesia, and drastic behavioral effects (depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, psychotic episodes and other changes in mood or personality).
The peripheral administration of levodopa is further complicated by the fact that only about 1-3% of administered levodopa actually enters the brain unaltered, the remainder being metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the blood-brain barrier. This means that levodopa must be given in large amounts when it is used alone. The co-administration of a peripheral dopadecarboxylase has been found to reduce the dosage requirements and some of the side effects, although only marginally.
Finally, certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to the timing of levodopa intake, and they are then referred to as wearing-off reactions or end-of-dose akinesia. In other instances, fluctuations in clinical state are unrelated to the timing of doses (on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. (Aminoff, “Parkinson's Disease and other Extrapyramidal Disorders”, in Harrison's Principles of Internal Medicine, 14th Ed. McGraw-Hill, (1998), pp. 2356-2359), and Katzung Basic & Clinical Pharmacology, 6th Ed., Appleton & Lange, Norwalk, Conn.).
It is well accepted in the art that many of the problems recited above result form the unfavorable pharmacokinetic properties of L-DOPA, and, more particularly, from its poor water solubility, bioavailability and fast degradation in vivo.
It was therefore suggested that the use of an L-DOPA derivative, which can release L-DOPA in vivo and is characterized by improved pharmacokinetic properties, might overcome the above limitations. Thus, U.S. Pat. Nos. 5,354,885 and 5,607,969 disclose a preparation and use of L-DOPA ethyl ester for the treatment of PD. Such an L-DOPA derivative is highly water-soluble and was thought to have pharmacokinetic properties that are highly favorable as compared with those of L-DOPA. However, it was found that this L-DOPA derivative undergoes a fast hydrolysis to L-DOPA before it reaches the brain, which downgrades its consistency and efficiency as a PD treatment.
As is well recognized in the art, and is further detailed hereinbelow, amides are typically stable compounds that undergo slower hydrolysis than their corresponding esters. Several L-DOPA amide derivatives are disclosed in Wiczk et al. (Chemical Physics Letters 341 (2001) 99-106). However, while Wiczk et al. have prepared these amide derivatives in order to evaluate the fluorescence quenching of tyrosine derivatives by amide group, and thus the use of fluorescent aromatic amino acids as internal probes in conformational analysis, the use of such derivatives in the treatment of Parkinson disease and related conditions have not been explored.
There is thus a widely recognized need for, and it would be highly advantageous to have, L-DOPA derivatives for the treatment of Parkinson disease and related conditions, devoid of the above limitations.